In FY12, we published our clinical results of a pilot study of allogeneic stem cell transplantation for patients with high-risk pediatric sarcomas. This study (NCI 02-c-0259) used a non-myeloablative allogeneic peripheral blood stem cell transplant for patients with matched sibling donors to treat patients with ultra-high risk pediatric solid tumors. We demonstrated that the approach was well tolerated with no treatment related mortality and also made the novel observation that patients with very high risk pediatric solid tumors experience increased chemoresponsiveness and prolonged survival despite recurrence post-allogeneic stem cell transplant. We also provided evidence for a favorable survival rate in patients without evidence for disease at the time of transplantation. These results provide evidence for heretofore unappreciated interactions between chemosensitivity and the immune milieu which is potentially exploitable in non-transplant settings and invite further studies of allogeneic stem cell transplant for very high risk pediatric solid tumors. To that end, in FY12, we initiated a second generation trial of allogeneic stem cell transplantation trial which built upon the lessons learned in 02-c-02590 discussed above. Briefly, while the 02-c-0259 platform was well tolerated, the incidence of GVHD was high enough to prevent any serious efforts at immune based therapies and we saw a very high risk of tumor recurrence. Thus, we developed a novel approach to increase antitumor effects in this settings using NK cells, which preclinical studies suggest will not cause GVHD. We published a novel approach of using artificial antigen presenting cells to generate highly activated NK cells in 2011. In this work, we demonstrated that inhibitory receptors were not able to inhibit the activity of these NK cells. Rather, activating signals, primarily comprising the family of natural cytotoxicity receptors mediate potent tumor killing, regardless of signaling via killer inhibitory receptors. On this basis, we have now initiated a second generation clinical trial of allogeneic stem cell transplantation in high risk pediatric malignancy that incorporates infusions of activated NK cell during the period of lymphopenia following stem cell transplant. This represents the first time such cells have been used in humans, pediatric or otherwise, and thus is highly novel. Thus far, six patients have received activated NK cells and we have observed interesting antitumor effects as well as some evidence to suggest that these cells may induce GVHD. Accrual to the trial is ongoing. In FY12 we nearly completed accrual to the only Phase I study of anti-CTLA4 in pediatrics, targeting patients with pediatric melanoma. We have seen evidence for a partial response in a patient with melanoma and some evidence for disease stabilization. We also have demonstrated that children experience significant autoimmune toxicity with this agent, perhaps earlier during the course of therapy. In FY12, we published our results of a Phase I study of HGS-ETR2, a TRAIL receptor agonist in pediatric patients with solid tumors. Results demonstrated tolerability of the agent, some preliminary evidence for activity as evidenced by stable disease and a biomarker response in hepatoblastoma as well as provocative evidence for enhanced activity of HGS-ETR2 in tumors that have been previously irradiated. Results are currently in Press in the Journal of Clinical of Oncology. Currently this drug is not available for further study but we are hopeful that there may be opportunities to study TRAIL receptor agonists in the future in pediatrics in combination with radiation and/or other modalities.We also have an open trial using a genetically engineered T cell receptor targeting children with sarcomas. Specifically, we will administer a T cell receptor targeting NY-ESO-1 in pediatric and adult patients with NY-ESO-1+HLA-A2+ synovial sarcoma. This trial seeks to reproduce promising results seen in a trial administering similar T cells with high dose IL2 to patients with sarcoma and melanoma and represents a collaboration with the University of Pennsylvania. Thus far, no patients have accrued although we have screened &gt; 15 patients for this study. We anticipate enrolling patients during the upcoming year.In FY12, we nearly completed treatment of patients on our study of consolidation immunotherapy for high-risk pediatric sarcomas. The trial directly translates our basic research by administering dendritic cell based tumor vaccines to patients with high-risk pediatric sarcomas rendered lymphopenic by standard chemotherapy. Patients also receive autologous lymphocytes depleted of suppressive T cells, rhIL7, and a helper antigen, keyhold limpet hemocyanin (KLH), to augment immune responses. This regimen is highly novel representing the first use of rhIL7 in children and the only current example of rhIL7 being used in the context of a tumor vaccine trial. A total of 44 patients have been enrolled and 29 patients have received autologous T cells that have been depleted to suppressor populations and dendritic cell vaccines pulsed with KLH and autologous tumor lysate. Twenty-four of the patients have also received adjuvant rhIL7. We have observed vigorous responses to KLH, modest immune responses to tumor lysate and potent immunorestorative effects of rhIL7. Of the remaining 15, 4 are ineligible due to insufficient collection of tumor lysate/lymphocytes and 11 are unable due to progressive disease during primary therapy. Results thus far demonstrate vigorous immune responses to KLH, and significant immune responses to tumor lysate, enhanced immune reconstitution compared to historical trials that did not utilize rhIL7, as well as promising rates of disease free and overall survival.